Antibody drug conjugates (ADCs) hold the promise as a target specific and effective treatment for a number of diseases e.g. bacterial infection and cancers, but at the same time with an improved systemic side effect profile.
The concept to combine a target specific antibody with a cytotoxic compound is very simple and elegant. An antibody is well known for its ability to recognize an antigen in specific manner and the often insufficient cell killing activity following an immune response, limited its therapeutic potential. On the other hand, cyctotoxic compounds are widely used in the treatment of cancers and their effectiveness are hindered by non-specific systemic adverse events associated with higher dose usage. The combination of an antibody with a cyctoxic compound can therefore lead to a therapeutic agent with enhancing efficacy to the antibody and reduced systemic side effects to the cytotoxic drug, attributing to the target specific delivery by the antibody and minimize of normal tissues from drug exposures.
One of the keys to the success of ADCs relies on the identification of suitable linkers that are stable during circulation in the blood stream, but rapidly cleave to release the cytotoxic compound at the target for cell killing activity. A demonstrated successful example is the linker, such as the one in Adcertris, which incorporates a lysosomal enzymatic cleavable peptide component. The C-terminal amide bond in this part of the linker that can be easily cleaved at target cells by lysosomal enzymes is essential to the drug releasing mechanism. Other amide bonds on the linker if undergo prematurely cleavage may lead to undesirable side effects (Formular B-1).

This application describes the replacement of the N-terminal amide bond of the lysosomal enzymatic cleavable peptide with an amide surrogate (Formullar B-2). This modification can further improved stability of the resulting ADCs in circulation.
